7-99767460-G-A

Variant names:

• chr7-99767460-G-A
• rs4646437
• NM_017460.6:c.671-202C>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_017460.6(CYP3A4):​c.671-202C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.292 in 152,112 control chromosomes in the GnomAD database, including 12,044 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as drug response (★★★).

• Frequency: Genomes: 𝑓 0.29 (12044 hom., cov: 32)
• Consequence: CYP3A4 NM_017460.6 intron
• Clinical Significance: drug response reviewed by expert panel O:1
• Conservation: PhyloP100: 0.192
• Publications: 126 publications found

Genes affected

CYP3A4 (HGNC:2637): (cytochrome P450 family 3 subfamily A member 4) This gene encodes a member of the cytochrome P450 superfamily of enzymes. The cytochrome P450 proteins are monooxygenases that catalyze many reactions involved in drug metabolism and synthesis of cholesterol, steroids and other lipids. This protein localizes to the endoplasmic reticulum and its expression is induced by glucocorticoids and some pharmacological agents. This enzyme is involved in the metabolism of approximately half the drugs in use today, including acetaminophen, codeine, cyclosporin A, diazepam, erythromycin, and chloroquine. The enzyme also metabolizes some steroids and carcinogens. This gene is part of a cluster of cytochrome P450 genes on chromosome 7q21.1. Previously another CYP3A gene, CYP3A3, was thought to exist; however, it is now thought that this sequence represents a transcript variant of CYP3A4. Alternatively spliced transcript variants encoding different isoforms have been identified. [provided by RefSeq, Aug 2020]

CYP3A4 Gene-Disease associations (from GenCC):

• vitamin D-dependent rickets, type 3

  Inheritance: Unknown, AD Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.71 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_017460.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CYP3A4	NM_017460.6	MANE Select	c.671-202C>T		intron	N/A	NP_059488.2
	CYP3A4	NM_001202855.3		c.671-205C>T		intron	N/A	NP_001189784.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CYP3A4	ENST00000651514.1	MANE Select	c.671-202C>T		intron	N/A	ENSP00000498939.1
	CYP3A4	ENST00000336411.7	TSL:1	c.671-202C>T		intron	N/A	ENSP00000337915.3
	CYP3A4	ENST00000652018.1		c.524-202C>T		intron	N/A	ENSP00000498733.1

Frequencies

GnomAD3 genomes AF: 0.291 AC: 44289 AN: 151994 Hom.: 12001 Cov.: 32

Gnomad AFR AF: 0.716

Gnomad AMI AF: 0.0714

Gnomad AMR AF: 0.193

Gnomad ASJ AF: 0.115

Gnomad EAS AF: 0.150

Gnomad SAS AF: 0.358

Gnomad FIN AF: 0.0880

Gnomad MID AF: 0.247

Gnomad NFE AF: 0.106

Gnomad OTH AF: 0.257

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.292 AC: 44388 AN: 152112 Hom.: 12044 Cov.: 32 AF XY: 0.289 AC XY: 21489 AN XY: 74362

African (AFR) AF: 0.716 AC: 29711 AN: 41472

American (AMR) AF: 0.193 AC: 2952 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.115 AC: 400 AN: 3466

East Asian (EAS) AF: 0.151 AC: 780 AN: 5180

South Asian (SAS) AF: 0.357 AC: 1722 AN: 4820

European-Finnish (FIN) AF: 0.0880 AC: 931 AN: 10584

Middle Eastern (MID) AF: 0.228 AC: 67 AN: 294

European-Non Finnish (NFE) AF: 0.106 AC: 7212 AN: 67994

Other (OTH) AF: 0.259 AC: 548 AN: 2116

Alfa AF: 0.155 Hom.: 11679

Bravo AF: 0.314

Asia WGS AF: 0.333 AC: 1156 AN: 3478

ClinVar

Significance: drug response

Submissions summary: Other:1

Revision: reviewed by expert panel

Submissions by phenotype

tacrolimus response - Metabolism/PK Other:1

Mar 24, 2021

PharmGKB

Significance: drug response

Review Status: reviewed by expert panel

Collection Method: curation

PharmGKB Level of Evidence 2A: Variants in Level 2A clinical annotations are found in PharmGKB’s Tier 1 Very Important Pharmacogenes (VIPs). These variants are in known pharmacogenes, implying causation of drug phenotype is more likely. These clinical annotations describe variant-drug combinations with a moderate level of evidence supporting the association. For example, the association may be found in multiple cohorts, but there may be a minority of studies that do not support the majority assertion. Level 2A clinical annotations must be supported by at least two independent publications. Drug-variant association: Metabolism/PK

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	6.4
DANN	Benign	0.31
PhyloP100		0.19
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs4646437; hg19: chr7-99365083;